ABSTRACT There is a fundamental gap in knowledge regarding the pathophysiology of urethral stricture disease (USD) and this gap is limiting innovation in the field. Our group's long-term goal is to develop non-surgical alternatives, and adjuvants, for this (historically) surgically managed disease process. Reaching this goal will require new knowledge about USD behavior. Here, we are proposing that understanding how inflammation affects stricture development and treatment outcomes will represent the first step towards field innovation and towards our goal. The rationale for such a pursuit lies in clinical observations made by the Trauma and Urologic Reconstruction Network of Surgeons (TURNS), where men with lichen sclerosus (LS) USD, a well- described inflammatory genital skin condition, were found to have significantly higher rates of comorbid, chronic conditions also associated with inflammation (e.g. metabolic syndrome). Further insights have revealed that inflammatory strictures have higher rates of treatment failure and more recently, the TURNS group showed that nearly 50% of ?idiopathic? USD had chronic inflammation in the specimen that had been previously unappreciated. In other words, what once was considered to be a relatively static, fibrotic disease process, may instead be a dynamic, and active process with ongoing inflammation, antigen presentation, and perhaps most importantly, potential targets for non-surgical treatments. Our central hypothesis is that both local and systemic inflammation plays a significant role in the development and propagation of USD. We will test this hypothesis with three specific aims: Aim 1 will characterize inflammatory profiles of 180 men (and 10 controls), as determined by urine, urethral wash and surgical tissue, of men undergoing anterior urethroplasty for USD, and we expect to find that differences in the clinical and inflammatory profiles will allow for patient cluster creation that may uncover unique pathophysiology. In Aim 2, we'll look at the systemic inflammation in these men, which will then allow comparison of the systemic and local inflammatory profiles to determine how they might influence one another. Finally, in Aim 3, the TURNS post-operative follow-up protocol will be used to determine how surgical success is related to inflammatory profiles. The approach is innovative because it harnesses the power of a clinical outcomes group (TURNS) to rapidly, and systematically, collect tissue from a relatively rare disease process, to analyze how the underlying mechanism of all disease (inflammation), might be specifically affecting the urethra. The significance of choosing inflammation to study is its ability to be modified elsewhere in the body and thus, the high likelihood that findings here will lead to clinical trials of non- surgical treatments. Ultimately, knowledge gained from this study has a strong potential to fundamentally alter the way we classify and treat this morbid, expensive and often debilitating disease process that can dramatically affect quality of life.